1. Field of the Invention
The present invention relates to compositions and methods of treatment for cardioprotection, and more particularly, to non-peptidic delta opioid receptor agonist compound(s) that mediate cardioprotective effects of ischemic preconditioning.
2. Description of the Related Art
Tissues deprived of blood and oxygen undergo ischemic necrosis or infarction with possible irreversible organ damage. In patients that survive a myocardial infarction exhibit a decreased viable myocardium due to ischemic damage. However, people who have angina previous to a heart attack, due to reduced oxygen flow to the heart muscle, show less tissue damage of the myocardium relative to those without angina. Thus, brief episodes of ischemia have the effect of protecting the myocardium from ischemic damage.
Ischemic preconditioning (PC) is a phenomenon, widely demonstrated in many species, including man, whereby the myocardium is protected from a major ischemic event by prior brief periods of ischemia or hypoxia followed by reperfusion or reoxygenation. The use of short duration, transient ischemia to protect against damage from a subsequent and more prolonged ischemic event has been demonstrated by Murry, et al. (Circulation, 1986: 74: 1124-1136). Test results show a reduction of tissue necrosis by approximately 30% in canine hearts that have been pretreated with short periods of ischemia prior to a major long-term event. The phenomenon of ischemic preconditioning has become of great clinical interest for treatment of patients with ischemic heart disease.
Ischemic preconditioning requires a physical reduction of the blood supply, which can be difficult or impractical for most patients. It has been found that exercise has the effect of ischemic preconditioning lasting approximately 24 hours but many patients are not physically capable of reaching the level of cardiac output required to reap the benefits of ischemic preconditioning. Intermittent ischemia induced by aortic cross-clamping prior to coronary bypass surgery has been used as a clinical application of ischemic preconditioning. It has been found that following a surgical procedure, cardiac output was significantly higher in patients who had myocardial preconditioning. Also preconditioned patients exhibited improved postoperative hemodynamics relative to patients without preconditioning. However, multiple potential problems can be associated with aortic cross clamping to effectuate reduced blood supply to the cardiac muscle, and thus it is desirable to have a treatment that potentiates ischemic preconditioning by pharmacological means.
It has been determined that a number of membrane receptors are involved in preconditioning including opioid receptors. The three main opioid receptor subtypes are μ, κ and δ. Delta opioid receptor stimulation mimics natural hibernation even in non-hibernating animals and has been reported to enhance tissue survival when oxygen delivery to the tissue is minimal. As such, delta opioid receptor stimulation has been shown to be involved in ischemic preconditioning. A number of studies have been conducted using peptidic and non-peptidic delta opioid receptor agonists to induce the effects of ischemic preconditioning. Schultz and Gross (U.S. Pat. No. 6,103,722) tested numerous non-peptidic delta opioid receptor compounds that exhibited ischemic preconditioning effects including (−)-2-Methyl-4a.α-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a.β-octahydroquinolino [2,3] isoquinoline (TAN67(−)); (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N diethylbenzamide (BW373U86); and (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). However, these non-peptidic compounds are not without problems, especially because these compounds are considered analgesics and several of the compounds are known to cause seizures in the dosed subject due to the passage of these compounds over the blood brain barrier.
As such, it is desirable to have a treatment that potentiates ischemic preconditioning by pharmacological means, which avoids the problems associated with reduced blood supply to the cardiac muscle and the potential of seizures caused by administration of some delta opioid receptor agonist compounds.